Suppression of APC/CCdh1 has subtype specific biological effects in acute myeloid leukemia

Abstract

// Daniel Ewerth 1, 2 , Andrea Schmidts 1 , Manuel Hein 1, 3 , Dominik Schnerch 1 , Arunas Kvainickas 1, 4 , Christine Greil 1 , Justus Duyster 1 , Monika Engelhardt 1 , Ralph Wäsch 1 1 Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany 2 Faculty of Biology, University of Freiburg, Freiburg, Germany 3 Present address: Department of Cardiology and Angiology II, University Heart Center Freiburg - Bad Krozingen, Faculty of Medicine, University of Freiburg, Bad Krozingen, Germany 4 Present address: Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany Correspondence to: Ralph Wäsch, email: ralph.waesch@uniklinik-freiburg.de Keywords: anaphase-promoting complex, Cdh1, ubiquitin-ligase, acute myeloid leukemia, differentiation Received: September 06, 2015      Accepted: June 09, 2016      Published: June 21, 2016 ABSTRACT The E3 ubiquitin ligase and tumor suppressor APC/C Cdh1 is crucial for cell cycle progression, development and differentiation in many cell types. However, little is known about the role of Cdh1 in hematopoiesis. Here we analyzed Cdh1 expression and function in malignant hematopoiesis. We found a significant decrease of Cdh1 in primary acute myeloid leukemia (AML) blasts compared to normal CD34+ cells. Thus, according to its important role in connecting cell cycle exit and differentiation, decreased expression of Cdh1 may be a mechanism contributing to the differentiation block in leukemogenesis. Indeed, knockdown (kd) of Cdh1 in HL-60 cell line (AML with maturation, FAB M2) led to less differentiated cells and a delay in PMA-induced differentiation. Acute promyelocytic leukemia (APL, FAB M3) is an AML subtype which is highly vulnerable to differentiation therapy with all-trans retinoic acid (ATRA). Accordingly, we found that APL is resistant to a Cdh1-kd mediated differentiation block. However, further depletion of Cdh1 in APL significantly reduced viability of leukemia cells upon ATRA-induced differentiation. Thus, low Cdh1 expression may be important in AML biology by contributing to the differentiation block and response to therapy depending on differences in the microenvironment and the additional genetic background.